tbuckley/cabot-search huggingface dataset:
The risks of thrombotic and bleeding events in patients receiving PEGylated asparaginase for treatment of acute lymphoblastic leukemia.
Authors: Ben Mautner, Eric Pierce, Joseph Mort, Samantha DiBenedetto, Leah Wells, Farid Ghamsari, Emily Morse, Amy Morris, Michael Kenneth Keng, Firas El Chaer
Journal: Journal of Clinical Oncology (2022)

e19015 Background: The prognosis of adult patients with acute lymphoblastic leukemia (ALL) has improved with the adoption of pediatric-inspired chemotherapy regimens. PEGylated asparaginase (PEG-Asp) is essential to these regimens. Although PEG-Asp is associated with an increased risk of coagulopathy, venous thromboembolism, and depletion of antithrombin III (AT3), there is limited data evaluating the risk of thrombosis and bleeding and optimal antithrombotic interventions in these patients are unknown. Methods: We performed a single-center retrospective study of patients ≥ 18 years-old who received PEG-Asp for B- or T-ALL at the University of Virginia between 2015 and 2020. The primary outcomes were the incidence of thrombosis and bleeding events. All patients received prophylactic AT3 repletion for activity level &lt;60% &amp; cryoprecipitate for fibrinogen &lt;100mg/dL. None received prophylactic anticoagulation. All received prednisone during induction at a median daily dose of 1 mg/kg. Results: We identified 57 patients who received PEG-Asp for ALL. Median age was 32 years (range 18-63). Five patients (8.8%) had a thrombotic event during induction versus five (16%) during post-induction. Four patients (7%) had a bleeding event during induction versus five (10%) during post-induction. The most common type of thrombosis was deep venous thrombosis, with the majority being catheter-associated. Pulmonary embolism and CNS thrombosis were less common. During induction, the median time to thrombotic event was 18 days after last PEG-Asp administration. 60% and 80% of patients received AT3 and cryoprecipitate, respectively. During post-induction, the median time to thrombotic event was 58 days after last PEG-Asp administration. 38% and 63% of the patients received AT3 and cryoprecipitate, respectively. There was one episode of major bleeding during induction and six during post-induction. Conclusions: Though the increase in thrombotic risk in adult patients receiving PEG-Asp is well-characterized, rates of reported thromboses vary widely. Studies examining bleeding risk associated with PEG-Asp regimens are even scarcer and with variable outcomes. There was a significant occurrence of both thrombotic and bleeding events associated with administration of PEG-Asp. More investigation into the relative thrombotic and bleeding risks associated with PEG-Asp is needed to determine optimal antithrombotic interventions in adult patients with ALL.[Table: see text]
Statins reduce mortality of patients with myelodysplastic syndromes.
Authors: Amber Afzal, Mark A. Fiala, Meagan Jacoby, Matthew Walter
Journal: Journal of Clinical Oncology (2022)

e19063 Background: Statins can inhibit cholesterol synthesis through inhibition of mevalonic acid synthesis, and reduce prenylation of proteins involved in tumor growth. Their anti-neoplastic potential has been explored for many malignancies (e.g., multiple myeloma) with improvement in progression free- and overall- survival. Preclinical data support anti-neoplastic activity of statins for myeloid malignancies. In this study, we examined the effect of statins on mortality of patients with myelodysplastic syndromes (MDS) in this nationwide retrospective cohort study. Methods: We identified patients diagnosed with MDS through ICD-O-03 codes in the SEER-Medicare database between 2007 and 2017. Statins users were required to have at least one claim for a statin prescription within 6 months prior to MDS diagnosis. Propensity score matching was done to identify non-statin users with a similar cardiovascular risk profile. We analyzed the effect of statins on mortality (from any cause) in a Cox proportional hazards model that adjusted for demographics, SEER-Medicare MDS Risk Score ( SMMRS comprises of age, comorbidities, MDS histological subtype, cytopenias, transfusion-dependence and hospital admissions), treatments for lower risk MDS (growth factors or lenalidomide), and higher risk MDS (hypomethylating agents/stem cell transplant). Results: Our cohort of 6878 MDS patients (3439 statin users and 3439 non-statin users) had a median age of 80 years at diagnosis, and most were Caucasians. Non-statin users were more likely to have higher risk MDS (by SMMRS) at diagnosis. Statins users had a 33% {95% Confidence Interval (CI) 25%-40%; p &lt;.001} lower risk of death than non-statin users. The beneficial effect of statins on mortality diminished over time (Table). Sub-group analysis (data not shown) showed a significant reduction in mortality with statin use in both patients with lower risk {low or intermediate-1 risk: Adjusted hazards ratio (aHR) 0.72; 95% CI 0.58-0.90; p = 0.003)} and higher risk {intermediate-2 or high-risk: aHR 0.67; 95% CI 0.59-0.76; p &lt; 0.001)} MDS (categorized by SMMRS). Conclusions: Use of statins at time of MDS diagnosis is associated with reduced mortality among these patients. The beneficial effect of statins on death from cardiovascular events and myeloid malignancy should be further explored in clinical trials enrolling MDS patients.[Table: see text]
High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease
Authors: Catherine Tcheandjieu, Ke Xiao, Helio Tejeda, Julie A. Lynch, Sanni Ruotsalainen, Tiffany Bellomo, Madhuri Palnati, Renae Judy, Derek Klarin, Rachel L. Kember, Shefali Verma, Goncalo Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris Economides, Katia Karalis, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Katherine Siminovitch, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Maria Sotiopoulos Padilla, Manasi Pradhan, Kia Manoochehri, Thomas D. Schleicher, Louis Widom, Sarah E. Wolf, Ricardo H. Ulloa, Amelia Averitt, Nilanjana Banerjee, Dadong Li, Sameer Malhotra, Deepika Sharma, Jeffrey C. Staples, Xiaodong Bai, Suganthi Balasubramanian, Suying Bao, Boris Boutkov, Siying Chen, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, George Mitra, Mona Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Kathie Sun, Jiwen Xin, Joshua Backman, Amy Damask, Lee Dobbyn, Manuel Allen Revez Ferreira, Arkopravo Ghosh, Christopher Gillies, Lauren Gurski, Eric Jorgenson, Hyun Min Kang, Michael Kessler, Jack Kosmicki, Alexander Li, Nan Lin, Daren Liu, Adam Locke, Jonathan Marchini, Anthony Marcketta, Joelle Mbatchou, Arden Moscati, Charles Paulding, Carlo Sidore, Eli Stahl, Kyoko Watanabe, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Marcus B. Jones, Jason Mighty, Lyndon J. Mitnaul, Aarno Palotie, Mark Daly, Marylyn Ritchie, Daniel J. Rader, Manuel A. Rivas, Themistocles Assimes, Philip Tsao, Scott Damrauer, James R. Priest
Journal: Nature Genetics (2022)
SVEP1 is a new regulator of arterial tone
Authors: GE Morris, MJ Denniff, RB Kostogrys, V Bountziouka, RD Rainbow, NJ Samani, TR Webb
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Introduction Vascular tone is regulated by the relative contractile state of vascular smooth muscle cells (VSMCs). Several integrins can directly modulate VSMC contraction by regulating calcium influx through L-type voltage-gated Ca2+ channels (VGCCs). Integrin α9β1 has been identified as preventing exaggerated airway bronchiole contraction. Genetic variants in ITGA9, which encodes the α9 subunit of integrin α9β1, and SVEP1, a ligand for integrin α9β1, are associated with elevated blood pressure, however, neither SVEP1 nor integrin α9β1 have a reported role in vasoregulation. Purpose To determine whether SVEP1 and integrin α9β1 regulate blood vessel contraction. Methods &amp; Results Animal experimentation was performed according to ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines and "the Principles of laboratory animal care". Immunocytochemical staining showed both ligand and receptor co-localised within the medial layer of the aorta, and in smooth muscle cells in the mesenteric artery. siRNA inhibition of SVEP1 or integrin α9β1 significantly enhanced real-time [Ca2+]i release in isolated human VSMCs to several Gαq/11-vasoconstrictors and to UTP in VSMCs isolated from Svep1+/- mice (Fig. 1A, n=5, P&amp;lt;0.0001). This enhanced cellular contraction was confirmed in blood vessels by wire myography where aortic rings and mesenteric arteries (Fig. 1B, n=10 P&amp;lt;0.0001) from Svep1+/- mice contracted at significantly higher levels than littermate controls. Similar responses were seen in aortic rings when integrin α9β1 was inhibited using the small molecule inhibitor BOP (n=10 P&amp;lt;0.001). Inhibition of VGCCs using nifidepine, or PKC using bisindolylmaleimide (I) prevented this enhanced contraction, suggesting this effect is mediated via VGCCs in a PKC dependent mechanism. Conclusions Our studies reveal a novel role for SVEP1 and integrin α9β1 in reducing vascular hyper-contractility in response to a range of vasoconstrictor agonists through an L-type voltage gated Ca2+ channel-mediated effect. This regulatory mechanism could suggest a possible explanation for the genetic associations with blood pressure, and provide a new treatment strategy for hypertension.
Real-world treatment patterns among veterans with nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Ahmad Sami Halwani, Vikas Patil, Deborah Morreall, Chunyang Li, Christina Yong, Sreevalsa Appukkutan, Jamie Partridge, Jay Jhaveri, Kelli Marie Rasmussen
Journal: Journal of Clinical Oncology (2022)

e17042 Background: Prostate cancer (PC) is the most common cancer diagnosed among U.S. Veterans. Non-metastatic castration-resistant prostate cancer (nmCRPC) occurs in patients who, despite having received androgen deprivation therapy, experience a rising prostate-specific antigen (PSA) and castrate testosterone levels, with no evidence of metastatic disease on radiographic imaging. Given the recent approval of novel antiandrogens, the treatment landscape for nmCRPC has rapidly evolved. Although there have been numerous clinical trials examining the safety and efficacy of these treatments, few studies have identified real-world treatment patterns among nmCRPC patients. Methods: We conducted a retrospective observational study using patient information obtained from the Veterans Affairs (VA) Clinical Cancer Registry and the VA Corporate Data Warehouse (CDW) to identify patients who were diagnosed with PC at the VA, and later developed nmCRPC, defined as having: (1) evidence of rising PSA, i.e., 2 consecutive increases in PSA concentration over a baseline value; (2) evidence of ongoing androgen deprivation consisting of a serum testosterone level of ≤50 ng/dL (≤2.0 nmol/L); and (3) no evidence of metastatic disease on radiology reports. Treatments were extracted from CDW pharmacy dispensation records and were indexed at nmCRPC diagnosis. Results: A total of 12,549 patients were diagnosed with nmCRPC and treated in the VA from 2006 to 2020; of these, 7,239 (58%) were white, 3,386 (27%) were black, 784 (6%) were Hispanic, and 1,140 (9%) other. Median age at PC diagnosis was 69 years, with most patients residing in the South 4,817 (38%). Of the 7,659 (61%) patients receiving first-line (1L) nmCRPC therapy, 5,508 (72%) received bicalutamide, 621 (8%) ketoconazole, 563 (7%) abiraterone, 492 (6%) enzalutamide, and 242 (3%) flutamide. Although bicalutamide remained the most frequently used 1L nmCRPC therapy regardless of year, the adoption of abiraterone and enzalutamide beginning in 2012 resulted in a decline of 1L bicalutamide from 80% of patients in 2006 to 43% in 2020. Ketoconazole was the second most common 1L nmCRPC therapy and the most common second-line (2L) and third line (3L) nmCRPC therapy. Of patients receiving 1L therapy, 2,244 (31%) received 2L therapy, and of these, 708 (32%) received 3L therapy. Conclusions: To our knowledge, this is the largest real-world cohort of nmCRPC patients treated in a nationwide equal-access health care system. Despite the recent approval of several nmCRPC treatments (apalutamide, darolutamide, enzalutamide) which have demonstrated improved metastasis-free survival and treatment-related quality of life, our real-world findings suggest that older, first-generation antiandrogens remain the predominant 1L treatment for nmCRPC patients.
Investigating novel roles for nesprin-1 and the LINC complex in Dilated Cardiomyopathy
Authors: S De Silva, N Catibog, C Shanahan, Q Zhang
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Cardiomyopathies are an important cause of heart failure and sudden cardiac death. Recent studies have demonstrated the importance of the "passive" mechanical components of cardiomyocytes (CMs) as new causes for dilated cardiomyopathy (DCM). Nesprin-1/-2 are highly expressed in skeletal and cardiac muscle and together with SUN (Sad1p/UNC84)-domain containing proteins form the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex at the nuclear envelope (NE), which, in association with lamin A/C and emerin, mechanically couples the nucleus to the cytoskeleton. We have recently identified novel nesprin-1 mutants in DCM patients, which cause LINC complex disruption, leading to defects in nuclear organisation and myogenesis in vitro. We aim to investigate mechanisms through which these mutations lead to DCM. Therefore, we have generated a nesprin-1 mutant R8253Q knock-in (KI) mouse line (equivalent to human SYNE1 R8272Q) as the first clinically relevant animal model. 2. R8272Q is in close proximity to the binding regions to microtubule (MT) associated proteins kinesin light chain-1/2 and Akap6 at the nuclear envelope, which is potentially in involved in MT organization. Preliminary mouse echocardiography data showed significantly reduced thickness of left ventricle (LV) posterior wall in diastole, and reduced % ejection fraction in the KIs at 15 weeks after birth, suggesting LV dysfunction and a tendency of DCM. Immunofluorescence (IF) of isolated adult cardiomyocytes (ACM) from KI mice showed perinuclear MT localization was significantly reduced, KLC-1/2 and AKAP6 were mislocalized from the NE and altered nuclear positioning. Therefore, we propose to investigate novel roles of nesprin-1 and the LINC complex in cardiomyocyte mechanotransduction using this KI model to explore roles of nesprin-1 in microtubule organization, nuclear positioning, and CM homeostasis, which will yield insights into signalling leading to DCM and heart failure as well as inform strategies for translational approaches.
The surgical learning curve for cancer control after robot-assisted radical prostatectomy
Authors: C.A. Bravi, P. Piazza, E. Mazzone, L. Sarchi, S. Scarcella, S. Puliatti, S. Knipper, P. Dell'Oglio, A. Galfano, N. Suardi, C. Terrone, R. Autorino, U. Falagario, G. Carrieri, A. Galosi, R. Schiavina, R. De Groote, M. Moschovas, V. Patel, A. Vickers, A. Briganti, F. Montorsi, A. Mottrie
Journal: European Urology (2022)
Insomnia in cancer patients.
Authors: Edith J. Mensah-Osman
Journal: Journal of Clinical Oncology (2022)

e18657 Background: As new treatments extend patient survival, the quality of their lives (QoL) grows in importance. QoL may differentiate alternative treatments, and QoL assessment has become a standard component of treatment evaluations. Sleep is a key component of QoL. Insomnia can worsen pain, fatigue, depression and cognitive impairments in cancer patients. Inappropriate treatments for insomnia can further worsen these and interact with chemotherapy medications. Recognizing this, in 2019 the American Society of Clinical Oncology identified Insomnia as a key patient-reported outcome performance measure (PRO-PM) for the National Quality Forum to consider. Methods: Through review of the scientific literature the project identified specific cancers and their treatments where treating Insomnia can have a significant impact on patient QoL. PubMed, Pharmapendium, and Science Direct databases were used. Search terms included “insomnia demographics, epidemiology of insomnia in cancer, insomnia in tumor types, cancer insomnia, insomnia associated hormonal treatment, insomnia in patients awaiting cancer diagnosis; insomnia in cancer care-givers, insomnia in cancer survivors, cancers treated with corticosteriods”. Original research articles in English that used human subjects between January 1, 1993 and January 31, 2020 were included. Results: Insomnia is associated with specific tumor types: brain tumors, breast cancer, gastrointestinal cancer, leukemia, lymphoma, multiple myeloma and terminal cancer. Autoimmune causes of insomnia in paraneoplastic syndromes. Insomnia is prevalent in oncology patients being evaluated, awaiting diagnosis and treatment. Age and gender are demographic factors associated with oncology insomnia. Insomnia is associated with specific antineoplastic agents. Corticosteroid use is associated with insomnia, before, during and after cancer treatment. Insomnia in cancer survivors starts during their treatment and may persist for years. Conclusions: Specific demographics, cancers and treatments are associated with insomnia. Insomnia often occurs in patients undergoing evaluations for cancer. Insomnia is often not recognized and not treated in oncology patients. Insomnia that is not addressed during cancer treatment often persists in cancer survivors. There is the need to investigate whether treating insomnia early in cancer patients during their course of treatment can reduce symptoms such as fatigue and improve their QOL.
ATRT-13. An integrative analysis of the ATRT proteome unravels novel drug targets and refines molecular subgrouping
Authors: Pascal Johann, Torsten Müller, Mathias Kalxdorf, Martin Hasselblatt, Michael C Frühwald, Stefan M Pfister, Jeroen Krijgsveld, Marcel Kool
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Atypical teratoid/rhabdoid tumors (ATRT) represent frequent brain tumors in infants. In recent years, large-scale landscaping efforts on the epigenome and transcriptome of these tumors have unravelled a high degree of heterogeneity and three major molecular subgroups, termed ATRT-TYR, ATRT-SHH,ATRT-MYC, have been identified. The ATRT-proteome, in turn, still represents a largely unchartered territory. METHODS: We have performed a peptide-based screening approach to characterize the proteome of 40 ATRTs and six ATRT cell-lines. All of these samples had matching methylation data available and 28 also corresponding gene expression data. RESULTS: Unsupervised clustering recapitulated the previously described ATRT groups, revealing also a clear split of the SHH-subgroup in a supratentorial (SHH_1) and an infratentorial subgroup (SHH_2). Overall, we identified 7265 proteins, of which 1320 were differentially expressed between the groups, with an enrichment of spliceosome associated terms in SHH_1 and integrins/cell adhesions molecules in SHH_2. ATRT-MYC displayed an overrepresentation of immune cell markers and the TYR subgroup an enrichment of PI3K- as well as mTOR-signaling. Particularly, genes that have previously been described as signature genes for the ATRT-groups such as FABP7 in ATRT-SHH and OTX2 and MITF in ATRT-TYR were among the highly correlating genes that were both expressed in the proteome and the gene expression datasets. On top of this, our analysis revealed highly differentially expressed drug targets such as the tyrosine-kinase MARCKS (overexpressed in ATRT-TYR) not previously identified in ATRT transcriptome data, which warrant investigation by in vitro drug tests. CONCLUSION: Our data reveal the importance of previously described regulatory hubs in the ATRT subgroups, but additionally highlight novel drug targets that merit further exploration. Currently, drug treatment experiments in ATRT cell lines are ongoing to validate these proteins as drug targets, ultimately aiming to establish new therapeutic strategies in this deadly disease.
Synergistically Detachable Microneedle Dressing for Programmed Treatment of Chronic Wounds (Adv. Healthcare Mater. 11/2022)
Authors: Tianqin Ning, Fenghe Yang, Danli Chen, Zhenzhen Jia, Rongqing Yuan, Zhenqin Du, Shuaiyin Liu, Yao Yu, Xiaochuan Dai, Xufeng Niu, Yubo Fan
Journal: Advanced Healthcare Materials (2022)
Recurrence risk stratification model for patients with stage I-III colorectal cancer based on clinicopathological and postoperative ctDNA predictors.
Authors: Jin Gu, Fuming Lei, Xiaodong Wang, Hui Chen, Wensheng Huang, Xiaomang He, Yuming Hong, Qingmin Zeng, Yanzhao Wang, Qingkun Gao, Zheping Yuan, Pengfei Niu, Dandan Huang, Zhaoya Gao, Changming Ding, Zhichao Zhai, Ke An, Shiqing Chen, Xiaochen Zhao, Yuezong Bai
Journal: Journal of Clinical Oncology (2022)

e15511 Background: The aim of this study was to propose a new kind of recurrence risk classification and further establish a prognostic model for resected stage I-III colorectal cancer (CRC). Methods: From 2017 to 2020, 142 patients diagnosed with stage I-III CRC at Peking University Shougang Hospital were recruited for this study. Tissues and paired white blood cells were analyzed with a 733-gene NGS panel, and peripheral plasma obtained 7-10 days after surgery was analyzed with a 127-gene ultra-deep target panel in a CLIA-certified laboratory. The relationship between the postoperative ctDNA status, clinicopathological features and recurrence-free survival (RFS) was identified by log-rank test and Cox regression analysis. Results: In total, 108 patients successfully completed both tissue and postoperative plasma NGS tests, of which 17 patients were postoperatively positive for ctDNA (tumor-informed, ≥1 somatic mutation). Postoperative ctDNA positivity was independently associated with poorer RFS (HR = 8.4, P &lt; 0.0001). Postoperative recurrence rates were significantly higher in ctDNA-positive patients than ctDNA-negative patients (76.5% vs 16.5%, P &lt; 0.0001). Univariate analysis showed that, in addition to ctDNA status, stage, vascular invasion, neural invasion, and preoperative CEA were all significantly associated with worse RFS (P &lt; 0.05). Furthermore, in a COX regression model, the contribution of these clinicopathological factors to RFS has been adjusted. The model showed good discrimination [the concordance index (c-index): 0.811] of recurrence. Clinically high-risk groups according to clinicopathological risk model had significantly poorer RFS than low-risk groups (HR = 10.6, P &lt; 0.001). In the clinicopathological high-risk group, ctDNA-positive patients can still further differentiate the higher risk of recurrence (HR = 3.7, P = 0.0012). There were similar trends in the clinicopathological low-risk group (HR = 6.1, P = 0.066). Combining the clinicopathological model and ctDNA, patients with either clinicopathological high-risk or ctDNA-positive had a significantly poorer RFS, compared with both clinicopathological low-risk and ctDNA-negative (HR = 12.9, P &lt; 0.0001). Conclusions: Postoperative ctDNA can independently predict the risk of recurrence in stage I-III CRC. Combining clinicopathological factors and ctDNA showed superiority for recurrence risk stratification over either alone. This recurrence risk stratification model may serve as a useful clinical tool to help clinicians determine individualized treatment plans for stage I-III CRC patients. However, the model still needs further external cohort validation.
The role of conservative combination therapies for active and stable Peyronie’s disease: A systematic review and meta-analysis
Authors: N. Pyrgidis, F.A. Yafi, I. Sokolakis, F. Dimitriadis, I. Mykoniatis, G.I. Russo, P. Verze, G. Hatzichristodoulou
Journal: European Urology (2022)